Academic literature on the topic 'Neuro-immune diseases'

Chronic obstructive airway diseases are characterized by airflow obstruction and airflow limitation as well as chronic airway inflammation. Especially bronchial asthma and chronic obstructive pulmonary disease (COPD) cause considerable morbidity and mortality worldwide, can be difficult to treat, and ultimately lack cures. While there are substantial knowledge gaps with respect to disease pathophysiology, our awareness of the role of neurological and neuro-immunological processes in the development of symptoms, the progression, and the outcome of these chronic obstructive respiratory diseases, is growing. Likewise, the role of pathogenic and colonizing microorganisms of the respiratory tract in the development and manifestation of asthma and COPD is increasingly appreciated. However, their role remains poorly understood with respect to the underlying mechanisms. Common bacteria and viruses causing respiratory infections and exacerbations of chronic obstructive respiratory diseases have also been implicated to affect the local neuro-immune crosstalk. In this review, we provide an overview of previously described neuro-immune interactions in asthma, COPD, and respiratory infections that support the hypothesis of a neuro-immunological component in the interplay between chronic obstructive respiratory diseases, respiratory infections, and respiratory microbial colonization.

Frequent diseases of the CNS, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and psychiatric disorders (e.g., schizophrenia), elicit a neuroinflammatory response that contributes to the neurodegenerative disease process itself. The immune and nervous systems use the same mediators, receptors, and cells to regulate the immune and nervous systems as well as neuro-immune interactions. In various neurodegenerative diseases, peripheral inflammatory mediators and infiltrating immune cells from the periphery cause exacerbation to current injury in the brain. Acetylcholine (ACh) plays a crucial role in the peripheral and central nervous systems, in fact, other than cells of the CNS, the peripheral immune cells also possess a cholinergic system. The findings on peripheral cholinergic signaling, and the activation of the “cholinergic anti-inflammatory pathway” mediated by ACh binding to α7 nAChR as one of the possible mechanisms for controlling inflammation, have restarted interest in cholinergic-mediated pathological processes and in the new potential therapeutic target for neuro-inflammatory-degenerative diseases. Herein, we focus on recent progress in the modulatory mechanisms of the cholinergic anti-inflammatory pathway in neuroinflammatory diseases.

The thioredoxin system, consisting of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, plays a fundamental role in the control of antioxidant defenses, cell proliferation, redox states, and apoptosis. Aberrations in the Trx system may lead to increased oxidative stress toxicity and neurodegenerative processes. This study reviews the role of the Trx system in the pathophysiology and treatment of Alzheimer’s, Parkinson’s and Huntington’s diseases, brain stroke, and multiple sclerosis. Trx system plays an important role in the pathophysiology of those disorders via multiple interactions through oxidative stress, apoptotic, neuro-immune, and pro-survival pathways. Multiple aberrations in Trx and TrxR systems related to other redox systems and their multiple reciprocal relationships with the neurodegenerative, neuro-inflammatory, and neuro-oxidative pathways are here analyzed. Genetic and environmental factors (nutrition, metals, and toxins) may impact the function of the Trx system, thereby contributing to neuropsychiatric disease. Aberrations in the Trx and TrxR systems could be a promising drug target to prevent and treat neurodegenerative, neuro-inflammatory, neuro-oxidative stress processes, and related brain disorders.

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 The P.N.E.I. (Psycho-Neuro-Endocrine-Immunology) approach is represented by the interdisciplinary concept of bidirectional cross-talk between the psycho-neuro-endocrine and immune systems, which can influence the immune response. The well-known Gut-Brain Axis and the Gut-Skin Axis can be merged in a bigger network- the Gut-Brain-Skin Axis, with complex regulation by cytokines, neuro-peptides, neuro-hormones and another messenger (signalling) molecules and maybe the most important modulator of the Gut-Brain-Skin Axis/ the gut microbiota. The role of gut bacterial homeostasis is very important, and the homeostatic imbalance of the immune response may be a relevant etiologic/pathophysiologic factor for extra-intestinal and intestinal inflammatory, allergic and autoimmune diseases. The Low Dose Cytokines Medicine (LDM) is an innovative therapeutic approach. It is based on the most advanced knowledge in molecular biology and low dose pharmacology with the primary outcome. The SKA (Sequential Kinetic Activation) technology, codified and standardised by GUNA S.p.a. -Italy- makes the low doses of signalling molecules able to be active even below the minimum dose classically considered as effective and the significative efficacy of orally administered low-dose signalling molecules is the most representative aspect of LDM. The Physiologic Nutraceuticals and the Low Dose Medicine are two of the most promising approaches for the treatment of skin diseases based on the rebalance of the immune response and the recovery of gut dysbiosis.

Immune cells patrol the brain and can support its function, but can we modulate brain–immune communication to fight neurological diseases? Here, we briefly discuss the mechanisms orchestrating the cross-talk between the brain and the immune system and describe how targeting this interaction in a well-controlled manner could be developed as a universal therapeutic approach to treat neurodegeneration.

L'accumulation neuronale de protéines tau hyperphosphorylées et agrégées (« pathologie tau ») est corrélée au déclin cognitif dans la maladie d'Alzheimer. Les mécanismes liant tau à la perte de mémoire demeurent néanmoins mal connus. Différentes données épidémiologiques et expérimentales suggèrent que la consommation régulière de caféine réduit le risque de développer la maladie d'Alzheimer ainsi que les lésions et déficits cognitifs associés. Les effets protecteurs de la caféine ont été attribués au blocage des récepteurs à l'adénosine A2A (A2ARs), qui sont retrouvés augmentés dans le cerveau des patients atteints de la maladie d'Alzheimer, en corrélation avec le développement de la pathologie tau et des déficits cognitifs. Ces observations suggèrent ainsi un lien entre la dysrégulation cérébrale des récepteurs A2A, le développement de la pathologie tau et des déficits de mémoire dans la maladie d'Alzheimer. De manière intéressante, les récepteurs A2A sont dérégulés à la fois au niveau neuronal mais aussi au sein des astrocytes, sans que l’impact respectif de ces changements sur l’évolution pathologique de la MA ne soit connu. Dans ce contexte, l’objet de ce travail de thèse est d'explorer la relation entre la dysrégulation des A2ARs, la pathologie tau et les troubles synaptiques/cognitifs associés, en reproduisant les dysrégulations neuronale et astrocytaire du récepteur dans un nouveau modèle transgénique de la maladie d'Alzheimer.Nous avons développé un modèle conditionnel (Tet-Off) permettant la surexpression du A2AR dans les neurones CaMKII+ ou dans les astrocytes GFAP+. Ce modèle a été croisé avec la lignée de souris THY-Tau22, qui développe progressivement une pathologie tau hippocampique associée à un déclin des fonctions mnésiques ainsi qu’à un développement de processus neuroinflammatoires et une perte synaptique. Dans les différents groupes expérimentaux, nous avons notamment évalué les conséquences de la surexpression neuronale ou astrocytaire des récepteurs sur le développement de la pathologie tau et les altérations fonctionnelles associées (apprentissage et mémoire). Ces travaux chez la souris s’accompagnent également d’investigations post-mortem chez des patients atteints de dégénérescences lobaires fronto-temporales présentant des agrégats de tau (FTLD-tau).Nos travaux démontrent d’une part une augmentation neuronale du récepteur A2AR dans le cortex temporal de patients atteints de FTLD-tau avec mutation du gène MAPT P301L, une tauopathie pure. D’autre part, la surexpression neuronale du A2AR chez les souris THY-Tau22, mimant les modifications observées chez les patients, conduit à une augmentation hippocampique de l'hyperphosphorylation de tau, associée à une perte des synapses glutamatergiques, en lien avec la production microgliale de protéines du complément C1q, conduisant à une aggravation des troubles de la mémoire. Parallèlement, nous montrons que la surexpression astrocytaire du A2AR exacerbe les altérations de mémoire spatiale des souris THY-Tau22, en lien avec une augmentation de la phosphorylation et de l'agrégation de tau ainsi que des processus neuroinflammatoires hippocampiques associés.L’ensemble de ces données suggèrent que la dysrégulation des A2ARs retrouvée chez les patients atteints de la maladie d'Alzheimer mais aussi de FTLD-tau contribue au développement des troubles cognitifs, en favorisant l’émergence de la pathologie Tau ainsi que les pertes synaptiques associées, via des changements délétères de la communication neuro-gliale. Ces données suggèrent ainsi que le blocage des récepteurs adénosinergiques A2A est une option thérapeutique à envisager plus avant dans le contexte des tauopathies<br>Neuronal accumulation of hyperphosphorylated and aggregated tau proteins (referred to as “tau pathology”) is correlated with cognitive decline in Alzheimer’s disease (AD) but the mechanisms underlying tau-induced memory deficits remain unclear. Epidemiological and experimental studies pointed out that chronic caffeine consumption reduces AD risk, associated lesions as well as related cognitive deficits. These protective effects were ascribed to the blockade of adenosine A2A receptors (A2ARs), which have been found upregulated in AD patient’s brains in correlation with tau pathology development and cognitive deficits. These observations suggest a link between A2AR dysregulation, tau pathology development and memory loss in AD. Interestingly, both neuronal and astroglial A2AR appear to be dysregulated in AD, but the specific impact of each cell-specific change on AD progression remain unknown. In this context, the goal of this PhD work is to get insights towards the relationship between A2AR dysregulation, tau pathology development and associated synaptic/cognitive deficits, by inducing neuronal or astrocytic A2AR upsurge in a new transgenic mouse model of AD.To address this question, we have developed a new conditional model (Tet-Off) allowing the A2AR overexpression in CaMKII-positive neurons or GFAP-positive astrocytes. This model was crossed with THY-Tau22 mice, which progressively develops a hippocampal Tau pathology associated with memory decline, associated with neuroinflammatory processes and synaptic loss. In the different experimental groups, we have evaluated the consequences of neuronal or astrocytic upsurge of the A2ARs towards tau pathology and functional impairments (learning and memory). In addition, we also investigated post-mortem tissue of patients with frontotemporal lobar degeneration with tau aggregates (FTLD-tau).First, we show a neuronal upsurge of A2AR in the temporal cortex of FTDL-tau patients with MAPT P301L mutation, a pure tauopathy. The neuronal upregulation of A2AR in THY-Tau22 mice, modelizing these pathological changes, led to an hippocampal increase of tau hyperphosphorylation, associated with glutamatergic synapse loss, linked to the accumulation of the microglial complement protein C1q, leading to the worsening of spatial memory impairments. Additionally, we found that astrocytic A2AR overexpression worsened spatial memory impairments of THY-Tau22 mice. These effects were associated with an increased Tau phosphorylation together with the upregulation of hippocampal neuroinflammatory processes.Altogether, these data suggest that A2AR dysregulation seen in the brain of AD and FTLD-tau patients contributes to the development of Tau-induced cognitive impairments by increasing tau pathology and associated synaptic loss through detrimental neuro-immune changes. These data suggest that the blockade of adenosinergic A2A receptors is a therapeutic option to consider in the context of tauopathies

Interactions between the immune system and the nervous system are currently underappreciated, assumed to play minor mechanistic roles in disease pathogenesis. In contrast, our laboratory has demonstrated the importance of this relationship with significant impact, initially in Type 1 Diabetes (T1D). The experiments presented here build on our previous work to provide insights into the etiology of Multiple Sclerosis (MS) and Type 2 Diabetes (T2D). Transient Receptor Potential Vanilloid-1 (TRPV1) is an ion channel expressed on peripheral sensory afferent neurons that fundamentally control T1D pathogenesis. Here we show that mice with genetic ablation of TRPV1 are protected from EAE progression, attributable to reduced central nervous system (CNS) leukocyte passage. The pathogenic role of TRPV1 in permeabilizing the blood-CNS barriers may also translate to MS, as patients with progressive disease show a significant mutation bias within the TRPV1 gene. We were simultaneously intrigued by the growing worldwide obesity epidemic, and we observed that obese mice develop more severe EAE compared to lean mice. This was mechanistically linked to an expansion of TH17 cells, driven by sustained rises of IL-6 in obese mice. This research implies new therapeutic opportunities for the many obese patients with diverse autoimmune diseases. Finally, the immune system, obesity, and T2D are functionally linked, and we contributed to research that uncovered a large presence of immune cells in adipose tissue that drive insulin resistance. Manipulation of T cells and B cells affects local inflammation as well as whole-body insulin resistance and glucose homeostasis. Intriguingly, auto-antibodies in insulin resistant individuals are specific for a number of unique proteins, including glial fibrillary acidic protein (GFAP), initially shown by our laboratory to play a key role in T1D progression. We further characterized the autoimmune and neuronal progression elements that steer disease pathogenesis, and observed that administration of a vaccine containing GFAP is able to dramatically reduce weight gain and insulin resistance in mice. The data presented in this thesis provide a number of novel, mechanistic observations linking the immune and nervous systems in disease, and implies several potential avenues for treatment.

That part of the clinical interface between neurology and general medicine occupied by inflammatory and immunological diseases is neither small nor medically trivial. Neurologists readily accept the challenges of ‘primary’ immune diseases of the nervous system: these tend to be focussed on one particular target such as oligodendrocytes or the neuro-muscular junction present in predictable ways, and are amenable as a rule to rational, methodological diagnosis, and occasionally even treatment. This is proper neurology.‘Secondary’ neurological involvement in diseases mainly considered systemic inflammatory conditions—for example, SLE, sarcoidosis, vasculitis, and Behçet’s—is a rather different matter. It may be difficult enough to secure such a diagnosis even when systemic disease has previously been diagnosed and new neurological features need to be differentiated from iatrogenic disease, particularly drug side effects or the consequences of immune suppression. But all the diseases mentioned may present with and confine themselves wholly to the nervous system; they may mimic one another, and pursue erratic and unpredictable clinical courses. In central nervous system disease, diagnosis by tissue biopsy is potentially hazardous and unattractive. Few neurologists enjoy excesses of confidence or expertise when faced with such clinical problems: the cautious diagnostician is perplexed, and the evidence-based neuroprescriber confounded. Unsurprisingly, great variations in approaches to diagnosis and management are seen (Scolding et al. 2002b).But rheumatologically inclined general, renal or respiratory physicians, comfortable when managing inflammation affecting their system or indeed other parts of the body designed to support the nervous system, are generally also ill at ease when faced with neurological features whose differential diagnosis may be large, particularly given the near universal diagnostic non-specificity of either imaging or CSF analysis.Here then is the subject material for this chapter: the diagnosis and management of central nervous system involvement in inflammatory and immunological systemic diseases (Scolding 1999a). In not one of these neurological conditions has a single controlled therapeutic trial been reported, and much that is published on these conditions is misleading or inaccurate. And yet the frequency with which the diagnosis is only confirmed or even first emerges at autopsy bears stark witness to both the severity and evasiveness of these disorders.

Behcet’s Disease (BD) is a multiorgan disorder characterized by oral and genital ulceration, uveitis, and dermatological symptoms. BD is most prevalent in the Mediterranean countries and East Asia, but also occurs in Europe and North America. The etiology remains unknown. Evidence suggests that BD is an autoimmune disorder with complex traits. Neuro-Behcet’s Syndome (NBS) develops in about 5% to 30% of patients with BD and presents with parenchymal or nonparenchymal pathology. The course of NBS is highly variable. Treatment strategies include modulations of the immune response and tissue degeneration, along with symptomatic medications. Main directions of current research include genomic studies, biomarker discovery, and inventive drug- development strategies.

Following exposure to a severe traumatic event, such as warfare, sexual assault, or traffic accidents, a person may develop post-traumatic stress disorder (PTSD). This psychiatric disorder is characterized by constant re-experiencing of the traumatic event, with disturbing thoughts, feelings, or dreams related to the events, as well as irritability and exaggerated stressor reactivity. The increase of “fight-or-flight” responses leads to chronic dysregulation of stress-responsive mechanisms, including hypothalamic-pituitary-adrenal (HPA) and sympathetic axis activation, as well as immune imbalance. PTSD has been associated with alterations in regulatory mechanisms of the HPA axis, low cortisol levels, a low-grade inflammatory profile, and activated immune cells. These systemic changes further increase the risk for inflammatory diseases. The underlying mechanisms of these abnormalities are not completely known, but they include alterations in cellular sensitivity to glucocorticoids and epigenetic changes. The current chapter summarizes the main neuro-immuno-endocrine alterations observed in PTSD.

Murine models are widely used in scientific research because they share many genetic similarities with humans, making them a valuable tool for studying various diseases. C57BL/6 is an experimental mouse model to study the demyelination and inflammation etiology of Multiple Sclerosis (MS). Intracranial inoculation of neurotropic murine β-coronavirus strain of Mouse hepatitis virus in C57BL/6 mice induces demyelination with or without axonal loss, providing many insights regarding the mechanism of MS as well as SARS-CoV-2 mediated pulmonary and neuro pathology in humans. By selectively using knockout mice in the wild-type C57BL/6 background, researchers can gain insights into the immunomodulatory nexus and can identify pathways involved in immune regulation which further can be efficiently studied with CD4-/-, CD40-/- and CD40L-/- mice. In addition, C57BL/6 mice can also be used to generate syngeneic mouse models to investigate the etiology and mechanism of various cancers, including ovarian cancer. Similarly, along with C57BL/6 mice, different immunocompromised mice models, such as nude mice, SCID mice, and NOD/SCID mice, can be used to study the etiology, host-tumour interaction, function of the microenvironment, and tumour heterogeneity in tumour metastasis.